Process for preparing amino crotonyl compounds

ABSTRACT

The invention relates to an improved process for preparing 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylam ino)-1 -oxo-2-buten-1 -yl]am ino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline and related aminocrotonyl compounds and the preparation of a suitable salt of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline for use as a pharmaceutically active substance.

The invention relates to an improved process for preparing aminocrotonylcompounds such as for example4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineand the physiologically acceptable salts thereof, particularly4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate, as well as4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate and the use thereof for preparing pharmaceutical compositions.

4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]-amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinehas the following structure:

and is already known from WO 02/50043, which describes compounds withvaluable pharmacological properties, including in particular aninhibiting effect on signal transduction mediated by tyrosinekinases andan inhibitory effect on signal transduction mediated by the EpidermalGrowth Factor receptor (EGF-R). Therefore, compounds of this type aresuitable for the treatment of diseases, particularly for the treatmentof tumoral diseases, diseases of the lungs and respiratory tract anddiseases of the gastrointestinal tract and bile duct and gall bladder.

WO 02/50043 discloses a method of preparation wherein aminocrotonylcompounds (IV) such as for example4-[(3-chloro4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineare prepared in a one-pot reaction from the corresponding anilinecomponent (II), bromocrotonic acid (Ill), oxalyl chloride and asecondary amine (see Diagram 1). Diagram 1:

In this process the yield was at most 50%. In addition, purification wasgenerally carried out by column chromatography. Therefore, the method ofpreparing4-[(3-chloro4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinewas not suitable on an industrial scale. Furthermore, the method had thedisadvantage that bromocrotonic acid is not commercially available inlarge amounts and also the corresponding methyl bromocrotonate is onlyavailable in a purity of approx. 80%. These circumstances also militateagainst the suitability of this process for the industrial production of4-[(3-chloro4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline.

In the light of the above disadvantages of the known method ofproduction, the aim of the present invention is to provide a processwhich allows the production of aminocrotonylarylamides, particularly4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,using highly pure starting materials which are readily available andwithout any great technical expenditure. This new process shouldtherefore also be suitable for synthesis on an industrial scale andhence for commercial application.

This aim is achieved by the process according to the invention forpreparing4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineand other aminocrotonyl compounds. In addition to being industriallypracticable with high yields the method of synthesis according to theinvention also has the advantages of very good chemical purities and alow cis content of less than 0.1%.

In the process according to the invention the corresponding aminoarylcompound (V) is reacted with a di-(C₁₋₄-alkyl)-phosphonoacetic acid,preferably with diethylphos-phonoacetic acid, in suitable solvents,after corresponding activation, preferably with 1,1-carbonyldiimidazole, 1,1 -carbonylditriazole or propanephosphonicanhydride, particularly preferably with 1,1-carbonyldiimidazole,according to Diagram 2. The solvent used may be for exampletetrahydrofuran (THF), dimethylformamide (DMF) or ethyl acetate.

The activation may be carried out by any possible method of amidelinking, i.e. for example with 1,1-carbonyidiimidazole,1,1-carbonylditriazole, DCC (N,N-dicyclohexylcarbodiimide), EDC(N′-(dimethylaminopropyl)-N-ethylcarbodiimide), TBTUO-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate,thiazolidine-2-thione or by conversion into the corresponding acidchloride, possibly using thionyl chloride. If desired the activation maybe carried out using organic bases such as triethylamine or pyridine,while DMAP (dimethylaminopyridine) may additionally be added. Suitablesolvents include DMF, THF, ethyl acetate, toluene, chlorinatedhydrocarbons or mixtures thereof.

In the formulae that follow

-   X denotes a methyne group or a nitrogen atom,-   Ra denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group    and-   R¹ denotes a straight-chain or branched C₁₋₄-alkyl group.

The process is preferably used for compounds wherein

-   X denotes a nitrogen atom,-   R_(a) denotes a 3-chloro-4-fluorophenyl group and-   R¹ denotes an ethyl group.

Diagram 2:

The arylamide (VI) thus obtained in a high yield and high purity isreacted with the corresponding 2-aminoacetaldehyde using suitableorganic or inorganic bases in the sense of a Wittig-Horner-Emmonsreaction (Diagram 3). This reaction may be carried out directly or afterisolation of the compound (VI), for example by precipitation by theaddition of tert-butylmethyl ether, for example. Suitable bases includefor example DBU (1,5-diazabicyclo[4.3.0]non-5-ene), sodium hydroxide andpotassium hydroxide, of which sodium hydroxide and potassium hydroxideare preferred and potassium hydroxide is particularly preferred. Insteadof the aldehyde a corresponding equivalent, e.g. a hydrate or acetal,may be used, from which the aldehyde is released (beforehand or insitu).

Diagram 3:

The acetals used may be for example compounds of the following generaltype:

wherein R² to R⁵ in each case represent a straight-chain or branchedC₁₋₄-alkyl group, while the groups may be identical or different.

-   Preferably-   R³ and R⁴ in each case represent a methyl group and-   R² and R⁵ in each case represent an ethyl group.

The aminocrotonylarylamide of formula (VII) thus obtained, for example4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineof formula (I), may then be converted into the salts thereof,particularly the physiologically acceptable salts thereof, by methodsknown per se. Preferably they are converted into fumarates, tartrates ormaleates. The dimaleate of4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineof structural formula (la) and the conversion of4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineinto its dimaleate as shown in Diagram 4 are particularly preferred. Todo this the compound (I) is dissolved in a suitable solvent, such as forexample methanol, isopropanol, n-butanol or ethanol, optionally with theaddition of water, preferably ethanol, and combined with crystallinemaleic acid or a maleic acid solution, with heating. When ethanol isused as solvent the work is preferably done at a temperature of between60 and 75° C. using an ethanolic maleic acid solution. The reactionconditions are preferably selected so that the desired salt crystallisesout as quickly as possible. Preferably approx. 2 equivalents of maleicacid are used. After crystallisation has set in the mixture is cooled toambient temperature, stirred and the crystals consisting of compound(la) are separated off. Diagram 4:

The starting compound of formula (V) may for example be prepared asfollows in accordance with methods known from the literature.

The quinoline components of formula (V), wherein X=CH, may be obtainedstarting from commercially obtainable 3-fluoro-6-nitrophenol (XIV) byalkylation, exchanging the fluorine atom for an amino group and reactingwith ethoxyacrylic acid esters, ethoxymethylene-cyanoacetic acid estersor ethoxymethylene-malonic acid esters (Diagram 5a).

The compound thus obtained (XVII) is then converted into the compound(XVIII) as described in Diagram 6 for the quinazoline analogue

Diagram 5a:

To prepare the compound (V) wherein X=N the following procedure is used:Starting from commercially obtainable 4-chloro-anthranilic acid (VIII;X=Cl) the quinazolinone (IX) is obtained by reaction withformamidine-acetate, and is then nitrogenated using sulphuric acid andconcentrated nitric acid (Diagram 5b). Alternatively,4-fluoro-anthranilic acid may also be used as the starting material.

Diagram 5b:

The desired regioisomer (X) of the nitrogenation products thus obtainedis then chlorinated, and the chlorination product (XI) is reacted insitu with the corresponding amine (Diagram 6).

Diagram 6:

The compound of formula (XII) thus obtained is reacted with(S)-(+)-3-hydroxytetrahydrofuran to form compound (XIII). Hydrogenationof compound (XIII) or compound (XVIII) from Diagram 5a then yields thestarting compound (V) (diagram 7).

Diagram 7:

The invention also relates to4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate. This salt is particularly suitable for pharmaceutical use asit exists in only one crystalline modification, which is moreoveranhydrous and very stable.

For pharmaceutical use an active substance not only has to exhibit thedesired activity, but must also conform to additional requirements inorder to be allowed to be used as a pharmaceutical composition. Theseparameters are to a large extent connected with the physicochemicalnature of the active substance.

Without being restrictive, examples of these parameters are thestability of effect of the starting material under various environmentalconditions, stability during production of the pharmaceuticalformulation and stability in the final medicament compositions. Thepharmaceutically active substance used for preparing the pharmaceuticalcompositions should therefore have a high stability which must beguaranteed even under various environmental conditions. This isabsolutely essential to prevent the use of pharmaceutical compositionswhich contain, in addition to the actual active substance, breakdownproducts thereof, for example. In such cases the content of activesubstance in pharmaceutical formulations might be less than thatspecified.

The absorption of moisture reduces the content of pharmaceuticallyactive substance on account of the weight gain caused by the uptake ofwater. Pharmaceutical compositions with a tendency to absorb moisturehave to be protected from damp during storage, e.g. by the addition ofsuitable drying agents or by storing the medicament in a damp-proofenvironment. In addition, the uptake of moisture can reduce the contentof pharmaceutically active substance during manufacture if themedicament is exposed to the environment without being protected fromdamp in any way. Preferably a pharmaceutically active substance shouldtherefore have only limited hygroscopicity.

As the crystal modification of an active substance is important to thereproducible active substance content of a preparation, there is a needto clarify as far as possible any existing polymorphism of an activesubstance present in crystalline form. If there are differentpolymorphic modifications of an active substance care must be taken toensure that the crystalline modification of the substance does notchange in the pharmaceutical preparation later produced from it.Otherwise, this could have a harmful effect on the reproducible potencyof the drug. Against this background, active substances characterised byonly slight polymorphism are preferred.

Another criterion which may be of exceptional importance under certaincircumstances depending on the choice of formulation or the choice ofmanufacturing process is the solubility of the active substance. If forexample pharmaceutical solutions are prepared (e.g. for infusions) it isessential that the active substance should be sufficiently soluble inphysiologically acceptable solvents. It is also very important for drugswhich are to be taken orally that the active substance should besufficiently soluble.

The problem of the present invention is to provide a pharmaceuticallyactive substance which not only is characterised by high pharmacologicalpotency but also satisfies the above-mentioned physicochemicalrequirements as far as possible.

This problem is solved by4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethyl-amino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate.

4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]-amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate has a melting point of 178° C. (cf. the thermoanalysis shownin FIG. 2). The crystalline4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate was investigated further by X-ray powder diffraction. Thediagram obtained is shown in FIG. 1. The following Table lists the dataobtained in this analysis: TABLE X-ray powder reflections andintensities (standardised) of the4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate 2-Θ d-value intensity [°][Å] I/I_(o) [%] 4.91 18.0 47 6.42 13.8 33 7.47 11.8 27 8.13 10.9 3010.37 8.53 30 11.69 7.56 2 12.91 6.85 20 13.46 6.58 3 13.66 6.48 2 14.945.93 11 16.58 5.34 12 17.19 5.15 36 17.87 4.96 5 19.43 4.57 38 19.914.46 100 20.84 4.26 13 21.33 4.16 21 21.58 4.12 12 22.25 3.992 15 22.943.873 32 23.67 3.756 9 24.82 3.584 7 25.56 3.482 37 26.71 3.335 9 27.463.245 4 28.37 3.143 8 30.71 2.909 3 29.31 3.045 4 29.57 3.019 4 31.322.854 10 32.31 2.769 4 33.10 2.705 5 33.90 2.643 1 34.84 2.573 2 35.712.512 1 36.38 2.467 1 36.96 2.430 1 37.99 2.367 2 39.94 2.255 5

In the preceding Table the value “2 Θ[°]” denotes the angle ofdiffraction in degrees and the value “d_(hkl)[Å]” denotes the specifieddistances in Å between the lattice planes.

The x-ray powder diagrams were recorded, within the scope of the presentinvention using a Bruker D8 Advanced diffractometer fitted with a PSDdetector and a Cu anode as the x-ray source (CuK_(α1) radiation,λ=1.5418 Å, 40 kV, 40 mA).

The following Examples are intended to illustrate the invention:

EXAMPLES Example 1

Diethyl {[4-(3-Chloro-4-Fluoro-Phenylamino)-7-((S)-Tetrahydrofuran-3-Yloxy)-Quinazolin-6-Ylcarbamoyl]-Methyl}-Phosphonate

3.58 kg of 1,1-carbonyldiimidazole (22.16 mol) are placed in 12.8 litresof tetrahydrofuran and at 40° C. combined with 4.52 kg (22.16 mol) ofdiethylphosphonoacetic acid dissolved in 6.5 litres of tetrahydrofuran.The mixture is stirred for 30 minutes at 40° C. The resulting solutionis referred to as solution A.

6.39 kg (17.05 mol) ofN⁴-(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamineare placed in 26.5 litres of tetrahydrofuran and at 40° C. combined withsolution A and stirred for 2 hours at 30° C. 64 litres oftert.-butylmethylether are added to the suspension and after cooling to20° C. the precipitate is removed by centrifuging. It is washed with amixture of 16 litres of tetrahydrofuran and 16 litres of tert.-butylmethylether and then with 32 litres of water and dried at 50° C.

Yield: 6.58 kg (69.8%) of white crystals, content: HPLC 99.1 Fl %

Example 2

(E)-4-Dimethylamino-But-2-Enoicacid-[4-(3-Chloro-4-Fluoro-Phenylamino)-7-((S)-Tetrahydrofuran-3-Yloxy)-Quinazolin-6yl]-Amide

5.6 litres of 30% hydrochloric acid (53.17 mol) are added to 4.4 litresof water. Then 4.28 kg of 95% (dimethylamino)-acetaldehyde-diethylacetal(26.59 mol) are added dropwise within 20 minutes at 30° C. The reactionsolution is stirred for 8 hours at 35° C. stirred, cooled to 5° C. andstored under argon. This solution is referred to as solution B.

4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 litresof water and cooled to −5° C. This solution is referred to as solutionC.

5.88 kg (10.63 mol) of diethyl((4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yloxy)-quinazoline-6-ylcarbamoyl)-methyl)-phosphonateand 0.45 kg of lithium chloride (10.63 mol) are placed in 23.5 litres oftetrahydrofuran and cooled to −7° C. The cold solution C is added within10 minutes. Then solution B is added at -7° C. within 1 hour. Afterstirring for a further hour at −5° C. the reaction mixture is heated to30° C. and combined with 15 litres of water. After cooling to 3° C. thesuspension is suction filtered, the precipitate is washed with water anddried. Yield: 5.21 kg of crude product, 100%, water content: 6.7%

The crystallisation of the crude product is carried out with butylacetate/methylcyclohexane

Yield: 78% purity HPLC 99.4Fl %, water content 5.4%

Example 3

(E)-4-Dimethylamino-But-2-EnoicAcid-(4-(3-Chloro-4-Fluoro-Phenylamino)-7-((S)-Tetra-Hydrofuran-3-Yloxy)-Quinazolin-6Yl)-AmideDimaleate

6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoicacid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6yl)-amideare placed in 84 litres of ethanol and heated to 70° C. and combinedwith a solution of 2.94 kg (25.31 mol) of maleic acid in 36 litres ofethanol. After crystallisation has set in, first the mixture is cooledto 20° C. and stirred for 2 hours, then for 3 hours at 0° C. Theprecipitate is suction filtered, washed with 19 litres of ethanol anddried in vacuo at 40° C.

Yield: 8.11 kg (91.5%)

melting point: 178° C.

¹H-NMR (CD₃OD): δ=2.47+2.27 (m+m, 2H), 2.96 (s, 6H), 4.03 (m, 2H),4.07+3.92 (m+m, 2H), 4.18+4.03 (m+m, 2H), 5.32 (m, 1H), 6.26 (s, 4H),6.80 (m, 1H), 6.99 (m, 1H), 7.27(s, 1H), 7.30 (t, 1H), 7.66 (m,1H), 7.96(dd,1H), 8.62 (s,1H), 9.07 (s, 1H) ppm

1. a process for preparing a compound of the formula (VII)

wherein x denotes a methyne group or a nitrogen atom, R_(a) denotes abenzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group and R³ and R⁴denote a straight-chain or branched C₁₋₄-alkyl group, comprising thefollowing synthesis steps: a) reacting a compound of the formula (V)

wherein X denotes a methyne group or a nitrogen atom and Ra denotes abenzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, in suitablesolvents after corresponding activation withdi-(C₁₋₄-alkyl)-phosphonoacetic acid and b) reacting the resultingcompound of the formula (VI)

wherein X denotes a methyne group or a nitrogen atom, R_(a) denotes abenzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group and R¹ denotes astraight-chain or branched C₁₋₄-alkyl group, with the aldehyde offormula

wherein R³ and R⁴ in each case represent a straight-chain or branchedC₁₋₄-alkyl group, while the groups may be identical or different, or acorresponding aldehyde equivalent, using suitable organic or inorganicbases.
 2. A process for preparing4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethyl-amino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,comprising the following synthesis steps: a) reactingN⁴-(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)-quinazoline-4,6-diaminein suitable solvents after corresponding activation withdi-(C₁₋₄-alkyl)-phosphonoacetic acid and b) reacting the resultingdialkylester{[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonatewith the aldehyde prepared in situ from the corresponding(dimethylamino)-acetaldehyde-dialkylacetal using suitable organic orinorganic bases.
 3. The process according to claim 2, wherein in step a)diethylphosphonoacetic acid is used as reagent.
 4. The process accordingto claim 1, wherein in step b) DBU (1,5-diaza-bicyclo[4.3.0]non-5-ene),sodium hydroxide or potassium hydroxide is used as base.
 5. The processaccording to claim 4, wherein in step b) potassium hydroxide is used asbase.
 6. A process for preparing the dimaleates of4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,comprising steps a and b according to claim 1 as well as the followingstep c): c) converting the resulting4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineinto the dimaleate by reacting with maleic acid in a suitable solvent,with heating.
 7. The process according to claim 6, wherein ethanol orisopropanol is used as solvent, optionally with the addition of water.8. The process according to claim 6, wherein at least 2 equivalents ofmaleic acid are used. 9.4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate.
 10. A pharmaceutical composition containing4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate optionally together with one or more inert carriers and/ordiluents.
 11. A method for treating benign or malignant tumours,diseases of the respiratory tract and lungs as well as for treatingdiseases of the gastrointestinal tract and the bile duct and gallbladder which comprises administering4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate.